Intramyocardial implantation of differentiated rat bone marrow mesenchymal stem cells enhanced by TGF-β1 improves cardiac function in heart failure rats

Abstract

The present study tested the hypotheses that i) transforming growth factor beta 1 (TGF-β1) enhances differentiation of rat bone marrow mesenchymal stem cells (MSCs) towards the cardiomyogenic phenotype and ii) intramyocardial implantation of the TGF-β1-treated MSCs improves cardiac function in heart failure rats. MSCs were treated with different concentrations of TGF-β1 for 72 h, and then morphological characteristics, surface antigens and mRNA expression of several transcription factors were assessed. Intramyocardial implantation of these TGF-β1-treated MSCs to infarcted heart was also investigated. MSCs were initially spindle-shaped with irregular processes. On day 28 after TGF-β1 treatment, MSCs showed fusiform shape, orientating parallel with one another, and were connected with adjoining cells forming myotube-like structures. Immunofluorescence revealed the expression of cardiomyocyte-specific proteins, α-sarcomeric actin and troponin T, in these cells. The mRNA expression of GATA4 and Nkx2.5 genes was slightly increased on day 7, enhanced on day 14 and decreased on day 28 while α-MHC gene was not expressed on day 7, but expressed slightly on day 14 and enhanced on day 28. Transmission electron microscopy showed that the induced cells had myofilaments, z line-like substances, desmosomes, and gap junctions, in contrast with control cells. Furthermore, intramyocardial implantation of TGF-β1-treated MSCs to infarcted heart reduced scar area and increased the number of muscle cells. This structure regeneration was concomitant with the improvement of cardiac function, evidenced by decreased left ventricular end-diastolic pressure, increased left ventricular systolic pressure and increased maximal positive pressure development rate. Taken together, these results indicate that intramyocardial implantation of differentiated MSCs enhanced by TGF-β1 improved cardiac function in heart failure rats.

Angiotensin II and TGF-β1 Induce Alterations in Human Amniotic Fluid-Derived Mesenchymal Stem Cells Leading to Cardiomyogenic Differentiation Initiation

“…In this study, these two biological compounds initiated alterations in human AF-MSCs leading towards the cardiac-like phenotype formation, in contrast to Gaafar and co-authors study where adipose tissue-derived MSCs were used (18). In agreement with previously published studies (7, 11, 12, 19, 20), our results demonstrate that angiotensin II and TGF- β 1, as well as decitabine, that was used as a positive control, together with morphological changes, upregulated the expression of the main cardiac genes-markers: early transcription factors NKX2-5 , TBX5 and GATA4 as well as structural genes of cardiomyocytes, such as MYH6 , TNNT2 and DES . Also, the increased expression of cardiac ion channels (sodium, calcium, potassium) genes observed with decitabine, angiotensin II and TGF- β 1, to a greater or smaller extent, suggests of governed cell fate to become functional cardiac myocytes upon maturation in vitro or in vivo (21).…”

“…Depending on the cellular and molecular environment, TGF- β 1 can also generate mature cells, for example, functional cardiomyocytes from cardiomyocytes progenitors (33). Also, several studies have successfully applied TGF- β 1 induced bone marrow MSCs to rodent infarcted myocardium where they assisted in the myocardial regeneration (12, 20) suggesting that all the features of mature cardiomyocytes probably are not necessary for successful clinical application. This suggests that AF-MSCs, pre-treated with angiotensin II or TGF- β 1, may also have potential clinical utility, for example, for transplantation into the myocardium, subsequent maturation and regeneration of the damaged tissue.…”

“…What is important, in vitro it was as effective as widely used chemical compound 5-azacytidine and even more effective than other biomolecules, for example, IGF-1, bFGF, dynorphin B, insulin or oxytocin (11). In contrast to angiotensin II, TGF- β 1 was also investigated in vivo by intramyocardial transplantation of differentiated rat bone marrow mesenchymal stem cells into the injured rat heart (12). Also, it was shown that TGF- β 1 had an effect on the contractile function of adult ventricular rat cardiomyocytes in vitro and in vivo by modulating laminin receptor 37/67 dependent regulation of cardiac performance signaling pathway (13).…”

Potential use of superparamagnetic iron oxide nanoparticles for in vitro and in vivo bioimaging of human myoblasts

“…There are variety of approaches to diminish these negative setbacks. First, is the use of various cytokines or other biological factors to accommodate the microenvironment of postinfarcted heart, promoting neovascularization 17 or cell myogenic differentiation 17 – 19 . Second, is the functional optimization of stem cells, such as stimulation of gap junctions formation in order to reduce arrhythmia 20 .…”

Effect of RGOs on the Efficacy of Nkx2.5 Transfected Bone Marrow Mesenchymal Stem Cells Transplantation in Treatment Heart Failure in Rats

“…Low concentrations of TGF-β1 synergistically enhance, whereas high concentrations decrease the vascular invasion of cultured endothelial cells induced by angiogenic factors. High doses of TGF-β1 may have a cytotoxic effect that lead to programmed cell death and senescence, which could result in a low differentiated rate [32]. This study found that RGOs not only strongly inhibited TGF-β1 and Collagen I mRNA expression, but also collaborated with Nkx2.5 to reduce the expression of Collagen I mRNA and the percentage of CVF.…”